TWI570124B - Quinoline derivatives as pde10a enzyme inhibitors - Google Patents

Description

Quinoline derivative as a PDE10A enzyme inhibitor

The present invention provides quinoline derivatives which are PDE10A enzyme inhibitors and are therefore suitable for the treatment of neurodegenerative and psychiatric disorders. In particular, the present invention provides compounds that are highly selective for PDE10 compared to other PDE subtypes. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compounds of the invention to treat disorders.

The cyclic nucleotide cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are used as intracellular second messengers that regulate a large number of processes in neurons. Intracellular cAMP and cGMP are produced by adenylate cyclase and guanylate cyclase, and are hydrolyzed by cyclic nucleotide phosphodiesterases (PDE) to their respective monophosphates via cyclic nucleotides. Nucleotide.

Phosphodiesterase 10A (PDE10A) is a bispecific phosphodiesterase that converts cAMP to AMP and converts cGMP to GMP (Soderling, S. et al., Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A is predominantly expressed in neurons in the striatum, n.accumbens, and olfactory tubercle (Kotera, J. et al. , Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger, TF et al, Brain Reseach, 2003, 985, 113-126).

Studies have shown that in the brain, PDE10 expression is highly expressed by caudate nucleus, medium spiny neuron (MSN) and corresponding neurons of the olfactory tubercle. MSN performance of two functions of classes of neurons: the performance of D ₁ dopamine receptor D ₁ and Expression D ₂ class of dopamine D ₂ like receptors. D ₁ neurons are part of the "direct" striatum output pathway and are widely used to promote behavioral responses. D ₂ neurons are part of the "direct" striatum output pathway that is used to suppress behavioral responses that compete with behavioral responses promoted by the "direct" pathway.

Dopamine D ₂ receptor antagonism is recognized in the treatment of schizophrenia. Since the 1950s, dopamine D ₂ receptor antagonism has been the backbone of psychiatric treatment and all effective antipsychotic drugs antagonize the D ₂ receptor. The role of D ₂ may be mediated primarily by neurons in the striatum, nucleus and olfactory nodules, as these regions receive the most dense dopamine-induced synapses and have strong D ₂ receptor expression (Konradi, C And Heckers, S. Society of Biological Psychiatry, 2001 , 50, 729-742).

Because PDE10A has a desirable performance profile in this article and has high and relatively specific expression in neurons in the striatum, nucleus and olfactory tubercle, PDE10A inhibition may have a similar effect to D ₂ receptor antagonism. Therefore, it has an antipsychotic effect.

While PDE10A inhibition is expected to mimic D ₂ receptor part antagonism, but can be expected to have different profiles. In addition to cAMP, the D ₂ receptor also has a signaling component (Neve, KA et al, Journal of Receptors and Signal Transduction 2004 , 24 , 165-205), so inhibition of cAMP via PDE10A can reduce strong D ₂ antagonism. The risk of side effects of the outer diameter of the cone is seen. Conversely, PDE10A inhibition may have some effect not seen in the context of D ₂ receptor antagonism. Also PDE10A expression in striatal neurons of the D ₁ receptor expression (Seeger, TF et al., Brain Research, 2003, 985, 113-126).

In addition, since the D ₁ receptor agonistic effect causes stimulation of adenylate cyclase and thus an increase in cAMP content, PDE10A inhibition may also have a role in mimicking the D ₁ receptor agonistic effect.

Finally, because PDE10A is a bispecific phosphodiesterase, PDE10A inhibition will not only increase cAMP in cells, but it is also expected to increase cGMP levels. cGMP activates many of the target proteins in cell-like cAMP and also interacts with the cAMP signaling pathway.

In short, PDEIOA inhibition may partially mimic D ₂ receptor antagonism and therefore have antipsychotic effect, but may be different from the profiles in the case of classical D ₂ receptor antagonists the profiles observed.

The PDE10A inhibitor papaverine was shown to be active in several antipsychotic models. Papaverine rigidity enhancing effect of D ₂ receptor antagonist fluoropiperidin of alcohol in rats, but without causing catalepsy alone (WO 03/093499). Papaverine reduces the high activity induced by PCP in rats, while the decrease in amphetamine-induced high activity is negligible (WO 03/093499). These models indicate that PDE10A inhibition has the potential for classical antipsychotics expected from the theoretical considerations outlined above. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of related neurological and psychiatric disorders. In addition, PDE10A inhibited subchronic PCP-induced attention deficit metastasis in reversing rats (Rodefer et al., Eur. J. Neurosci. 2005 , 4 , 1070-1076). This model suggests that PDE10A inhibition can alleviate cognitive deficits associated with schizophrenia.

The tissue distribution of PDE10A indicates that a PDE10A inhibitor can be used to increase cAMP and/or cGMP content in cells expressing PDE10A enzymes (specifically, neurons including basal ganglia), and the PDE10A inhibitor of the present invention will therefore be suitable for treatment A variety of neuropsychiatric conditions involving the basal ganglia, such as neurological and psychiatric disorders, schizophrenia, bipolar disorders, psychosis, obsessive-compulsive disorder, and addiction, and may have undesired and current commercial treatments The benefits of the side effects associated with the law.

Furthermore, the latest announcement (WO 2005/120514, WO 2005012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873) suggests that PDE10A inhibitors may be suitable for the treatment of obesity and non-insulin dependent diabetes.

In addition, recent publications indicate that PDE10A inhibitors may be suitable for the treatment of Huntingtons Disease (Giampa et al, PLoS One 2010, 5 (10), Giampa et al, Neurobiology of Disease (2009), 34(3), 450-456, Hebb et al., Current Opinion in Pharmacology 2007, 7(1), 86-92).

It is disclosed in WO 05/03129 and WO 05/02579 that pyrrolodihydroisoquinoline and variants thereof are inhibitors of PDE10. Piperidinyl substituted quinazolines and isoquinolines as PDE10 inhibitors are disclosed in WO 05/82883. WO 06/11040 discloses substituted quinazoline and isoquinoline compounds as inhibitors of PDE10. US 20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazolines and isoquinolines as potent phosphodiesterase (PDE) inhibitors. In particular, US 20050182079 relates to such compounds which are selective inhibitors of PDE10. Similarly, US 20060019975 discloses piperidine derivatives of quinazolines and isoquinolines as potent phosphodiesterase (PDE) inhibitors. US 20060019975 also relates to compounds which are selective inhibitors of PDE10. WO 06/028957 discloses the use of an inhibitor of PDE 10 for the treatment of psychotic and neurological syndromes A morphine derivative. W009/152825 discloses phenylimidazole derivatives as compounds which are inhibitors of PDE10.

However, such disclosures do not relate to the compounds of the invention, which are structurally unrelated to any of the known PDE10 inhibitors (Kehler, J. et al., Expert Opin. Ther , Patents 2007 , 77, 147-158), and inventors It has been found to be a highly active and selective PDE10A enzyme inhibitor.

The present invention provides a compound which is a PDE10A enzyme inhibitor and is therefore suitable for the treatment of neurodegenerative and/or psychiatric disorders, which is not effective in all patients. Therefore, there is still a need for alternative treatments.

It is an object of the present invention to provide a compound which is a selective PDE10A enzyme inhibitor.

Another object of the present invention is to provide compounds having such activity and having improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.

Another object of the present invention is to provide an effective treatment, particularly long-term treatment, for a human patient without causing side effects commonly associated with current therapies for neurological and psychiatric disorders.

Other objects of the present invention will become apparent after reading this specification.

Specific examples of invention

In a first specific example (E1), the invention relates to a compound of formula I: Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are individually selected from the group consisting of hydrogen, hydroxy, cyano, C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, halogen, methylene Dioxy, difluoromethylenedioxy and ethylenedioxy wherein -L- is a linker selected from the group consisting of -CH ₂ -CH ₂ - and -CH=CH- wherein the HET is selected from the group consisting of : Wherein one or more carbon-bonded hydrogens in the HET may be substituted with up to three substituents R7, R8 and R9 individually selected from the group consisting of: C ₁ -C ₆ alkyl; halogen; cyano, halo (C) ₁ -C ₆ )alkyl; aryl, alkoxy and C ₁ -C ₆ hydroxyalkyl and wherein * represents a point of attachment, its tautomers and pharmaceutically acceptable salts, and polymorphic forms thereof .

In a specific example (E2) of the specific example (E1), one or more of R1 to R6 are selected from the group consisting of C ₁ -C ₃ alkyl substituted by one or more F and not Substituted C ₁ -C ₃ alkyl.

In a specific example (E3) of the specific example (E1) or (E2), one or more of R1 to R6 are selected from the group consisting of methyl, ethyl, propyl, isopropyl, and Fluoromethyl, difluoromethyl and trifluoromethyl.

In a specific example (E4) of the specific example (E1), one or more of R1 to R6 are selected from the group consisting of methoxy, difluoromethoxy and trifluoromethoxy.

In a specific example (E5) of the specific example (E1), one or more of R1 to R6 are selected from the group consisting of fluorine and chlorine.

In a specific example (E6) of any one of the specific examples (E1) to (E5), -L- is -CH ₂ -CH ₂ -

In a specific example (E7) of any one of the specific examples (E1) to (E5), -L- is -CH=CH-

In a specific example (E8) of any one of the specific examples (E1) to (E7), the HET is selected from the group consisting of: Wherein HET is replaced by one or more of R7-R9 as needed, and wherein * represents a point of attachment.

In a specific example (E9) of any one of the specific examples (E1) to (E8), the HET is substituted with a substituent R7 selected from the group consisting of C ₁ -C ₆ alkyl, such as A a halogen; such as chlorine or bromine; a cyano group; a halogen (C ₁ -C ₆ ) alkyl group such as a trifluoromethyl group; an aryl group such as a phenyl group; and a C ₁ -C ₆ hydroxyalkyl group such as CH ₂ CH ₂ OH.

In a specific example (E10) of any one of the specific examples (E1) to (E8), the HET is substituted with two substituents R7 and R8 which are individually selected from the group consisting of C ₁ -C ₆ alkyl, such as Methyl; halogen, such as chlorine or bromine; cyano; halo (C ₁ -C ₆ ) alkyl, such as trifluoromethyl; aryl, such as phenyl; and C ₁ -C ₆ hydroxyalkyl, such as CH ₂ CH ₂ OH.

In a specific example (E11) of any one of the specific examples (E1) to (E8), the HET is substituted with three substituents R7, R8 and R9 which are individually selected from the group consisting of C ₁ -C ₆ alkyl , such as methyl; halogen, such as chlorine or bromine; cyano; halo (C ₁ -C ₆ ) alkyl, such as trifluoromethyl; aryl, such as phenyl; and C ₁ -C ₆ hydroxyalkyl, Such as CH ₂ CH ₂ OH.

In a specific example (E12) of any one of the specific examples (E1) to (E8), HET is unsubstituted.

In a specific example (E13) of any one of the specific examples (E1), (E9), (E10) and (E11), the HET is substituted with at least one C ₁ -C ₆ alkyl group (such as a methyl group)

In a specific example (E14) of any one of the specific examples (E1) to (E11), the HET is selected from the group consisting of: (5,7-dimethyl-imidazo[1,2-a Pyrimidin-2-yl), 5,7-dimethyl-triazolo[1,5-a]pyrimidin-2-yl), (5,8-dimethyl-[1,2,4]tri Oxazo[1,5-a]pyridin -2-yl), (8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl) and 5,8-dimethyl- [1.2.4] Triazolo[1,5-a]pyridin-2-yl).

In a specific embodiment (E15) of the specific example (E1), the compound is selected from the group of compounds listed in Table 1.

In a specific example (E16) of any one of the specific examples (E1) to (E15), the present invention provides a compound of the formula I or a pharmaceutically acceptable salt thereof which is suitable for use as a pharmaceutical.

In a specific example (E17) of any one of the specific examples (E1) to (E15), the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, Diluent or excipient.

A specific example (E18) of any one of the specific examples (E1) to (E15) The present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a neurodegenerative disorder or a psychiatric disorder.

Further, in a specific example (E19) of any one of the specific examples (E1) to (E15), the present invention provides a method of treating a subject suffering from a neurodegenerative disorder, comprising administering to the subject And a therapeutically effective amount of a compound of formula I.

In a specific example (E20) of any one of the specific examples (E1) to (E15), the present invention provides a method of treating a subject suffering from a psychiatric condition, comprising administering to the subject a therapeutically effective amount A compound of formula I.

In a specific example (E21) of any one of the specific examples (E1) to (E15), the present invention provides a subject for treating a drug addiction such as alcohol, amphetamine, cocaine or opiate addiction. method.

In a specific example (E22), the invention relates to a compound of formula I: Wherein R1-R6 and HET are as described in any one of the previous specific examples (E1) to (E14) and -L- is a linker selected from the group consisting of -S-CH ₂ -, -CH ₂ -S- And -C≡C-.

Substituent definition

As used in the context of the present invention, the terms "halo" and "halogen" are used interchangeably and mean fluoro, chloro, bromo or iodo.

The term "C ₁ -C ₆ alkyl" refers to a straight or branched chain saturated hydrocarbon having from one to six (inclusive) carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2- Methyl-1-butyl and n-hexyl. The expression "C ₁ -C ₆ hydroxyalkyl" refers to a C ₁ -C ₆ alkyl group as defined above which is substituted by a hydroxy group. The term "halo(C ₁ -C ₆ )alkyl" refers to a C ₁ -C ₆ alkyl group, as defined above, substituted with up to three halogen atoms, such as trifluoromethyl.

The expression "C ₁ -C ₆ alkoxy" means a straight or branched chain saturated alkoxy group having from one to six (inclusive) carbon atoms and having an open atomic valence on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentyloxy, and n-hexyloxy. The alkoxy group may optionally be substituted with up to three halogen atoms, such as trifluoromethoxy.

The term "C ₃ -C ₈ cycloalkyl" generally means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The expression "C ₁ -C ₆ alkyl(C ₃ -C ₈ )cycloalkyl" refers to a C ₃ -C ₈ cycloalkyl group as defined above which is substituted by a straight or branched C ₁ -C ₆ alkyl group. Examples of such groups include, but are not limited to, cyclopropylmethyl.

The term "heterocycloalkyl" refers to a four to eight membered ring containing carbon atoms and up to three N, O or S atoms, with the proviso that the four to eight membered rings do not contain adjacent O or adjacent S atoms. Open valences are on heteroatoms or carbon atoms. Examples of such groups include, but are not limited to, azetidinyl, oxetane, piperidine Base, morpholinyl, thiomorpholinyl and [1,4]diazepanyl. The term "hydroxyheterocycloalkyl" refers to a heterocycloalkyl group as defined above which is substituted by a hydroxy group. The term "C ₁ -C ₆ alkyl-heterocycloalkyl" refers to a heterocycloalkyl group as defined above which is substituted by C ₁ -C ₆ alkyl. Examples of such groups include, but are not limited to, tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl.

The term "aryl" refers to a phenyl ring which is optionally substituted with a halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a halo(C ₁ -C ₆ )alkyl group as defined above. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl.

The term "C ₁ -C ₆ arylalkyl" refers to an aryl group as defined above which is substituted by a straight or branched C ₁ -C ₆ alkyl group. Examples of such groups include, but are not limited to, benzyl and 4-chlorobenzyl.

In another embodiment, one or more hydrogen atoms of the compound of Formula I have been deuterium substituted.

In the context of this application, it should be understood that "R1-R6", "R1 to R6" and "R1, R2, R3, R4, R5 and R6" have the same meaning.

Additionally, the invention further provides certain specific examples of the invention, which are described below.

In a particular embodiment of the invention, the compound of formula I is selected from the following specific compounds listed in Table 1 in free base form, one or more tautomers thereof, or a pharmaceutically acceptable salt thereof. Table 1 lists the compounds of the present invention and as "PDE10A inhibition assay" corresponding IC ₅₀ values of the measurement section. Each compound constitutes an individual embodiment of the invention.

It is to be understood that the various aspects, specific examples, embodiments, and features of the invention herein are claimed, or claimed in any combination, as illustrated by the following non-limiting examples.

In a particular embodiment of the invention, the compounds of the invention have an IC ₅₀ value of less than 50 nM, such as in the range of 0.2-20 nM, in particular in the range of 0.2-10 nM, such as in the range of 0.2-5 nM. Within the scope.

Pharmaceutically acceptable salt

The invention also includes salts of the compounds, usually pharmaceutically acceptable salts. These salts comprise pharmaceutically acceptable acid addition salts. The acid addition salt contains a mineral acid as well as a salt of an organic acid.

Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, amine sulfonic acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid. , maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, Pamo (pamoic) acid, bismethylene salicylic acid, ethane disulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, bran Amine acids, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, and 8-halotheophylline, such as 8-bromophylline and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed below: Berge, SM et al, J. Pharm . Sci . 1977, 66, 2, The content is incorporated herein by reference.

Furthermore, the compounds of the invention may exist in unsolvated as well as solvated forms (with pharmaceutically acceptable solvents such as water, alcohols and the like). In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

Pharmaceutical composition

The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a particular compound disclosed in the experimental part herein and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient, in single or multiple doses. The pharmaceutical compositions of the present invention may be formulated according to conventional techniques using pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, such as the techniques disclosed below: Remington: The Science And Practice of Pharmacy, 19th edition, edited by Gennaro, Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, transpulmonary, topical (including buccal and sublingual), transdermal, intracranial, peritoneal Internal, transvaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition being treated, and the active ingredient.

The pharmaceutical composition for oral administration comprises a solid dosage form such as a capsule, a lozenge, a dragee, a pill, a lozange, a powder, and a granule. appropriate The compositions may be prepared with a coating, such as an enteric coating, or they may be formulated to provide controlled release of the active ingredient, such as sustained or sustained release, according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

The pharmaceutical compositions for parenteral administration comprise sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders which are intended to be reconstituted in sterile injectable solutions or dispersions before use. Other suitable forms of administration include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, and implants.

Typical oral doses range from about 0.001 mg/kg to about 100 mg/kg body weight per day. Typical oral doses are also in the range of from about 0.01 mg/kg to about 50 mg/kg body weight per day. Typical oral doses are further in the range of from about 0.05 mg/kg to about 10 mg/kg body weight per day. Oral doses are usually administered in one or more doses per day, usually one to three doses. The precise dose will be readily apparent to the person who is familiar with the frequency and mode of administration, the sex, age, weight and general condition of the subject being treated, the condition being treated and the nature and severity of any accompanying disease to be treated and those skilled in the art. Depending on other factors.

Formulations may also be presented in unit dosage form by methods known to those skilled in the art. For illustrative purposes, typical unit dosage forms for oral administration may contain from about 0.01 mg to about 1000 mg, from about 0.05 mg to about 500 mg, or from about 0.5 mg to about 200 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscular, and the like, the typical dose is about one-half of the dose administered orally.

The invention also provides a method of making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I with at least one pharmaceutically acceptable carrier or diluent. In a specific embodiment of the present invention, the compound used in the above method is an experimental part of the present invention. Specific compounds disclosed.

The compounds of the invention are generally utilized in the form of a free substance or in the form of a pharmaceutically acceptable salt thereof. An example is an acid addition salt of a compound having a free base effect. When a compound of formula I contains a free base, such salts are prepared in a conventional manner by treatment of a solution or suspension of the free base of formula I with a molar concentration equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.

For parenteral administration, a solution of a compound of formula I in a sterile aqueous solution, aqueous propylene glycol solution, aqueous vitamin E solution or sesame oil or peanut oil may be employed. It is desirable to buffer such aqueous solutions as necessary and the liquid diluent first becomes isotonic with sufficient saline or glucose. Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I can be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyethylene oxide, and water. Similarly, the carrier or diluent may comprise any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. A pharmaceutical composition formed by combining a compound of formula I with a pharmaceutically acceptable carrier is then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations are preferably presented in unit dosage form by methods known in the art of pharmacy.

Formulations suitable for oral administration can be presented in individual unit form, such as capsules or lozenges, each containing a predetermined amount of active ingredient, and optionally Suitable for excipients. In addition, the orally acceptable formulations may be in the form of a powder or granule, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be placed in a hard gelatin capsule in the form of a tablet, in the form of a powder or a pellet or it may be in the form of a throat or an ingot. The amount of solid carrier will vary widely, but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.

The pharmaceutical compositions of the present invention can be prepared by conventional methods in the art. For example, a tablet may be prepared by mixing the active ingredient with a conventional adjuvant and/or diluent, and then compressing the mixture in a conventional tablet machine to prepare a tablet. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive commonly used for such purposes may be used, such as coloring agents, flavoring agents, preservatives, and the like, with the proviso that they are compatible with the active ingredient.

Therapeable effective amount

In the context of the present invention, the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention involving administration of the compound. A quantity sufficient to achieve this is defined as a "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury and the weight and general condition of the subject. It will be appreciated that determining the appropriate dosage can be accomplished using conventional experiments, by constructing a matrix of values and different points in the test matrix, all within the general skill of the trained physician.

In the context of the present invention, the term "treatment" means the management and care of a patient for the purpose of combating a condition, such as a disease or condition. The term is intended to encompass patients suffering from The complete range of treatment for a given condition, such as administration of the active compound to relieve symptoms or complications, delaying the progression of the disease, condition or condition, to alleviate or alleviate symptoms and complications, and/or to cure or eliminate the disease, condition Or a condition as well as a prophylaxis, wherein prevention is understood to mean managing and caring for a patient to achieve a fight against a disease, condition or condition and including administering an active compound to prevent symptoms or complications. However, prophylactic (prophylactic) and therapeutic (consistent) treatments are two separate aspects of the invention. The patient to be treated is preferably a mammal, specifically a human.

Treatment of illness

As mentioned above, the compound of formula I is a PDE10A enzyme inhibitor and is therefore suitable for the treatment of related neurological and psychiatric disorders.

Accordingly, the present invention provides a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for use in the treatment of a human neurodegenerative disorder, a psychiatric disorder or a drug addiction, and a pharmaceutical composition comprising the same.

In one embodiment of the invention, the neurodegenerative disorder or condition relates to neurodegeneration of a human striatum mid-spine spine neuron. In a particular embodiment of the invention, the neurodegenerative disorder or condition is Huntington's disease. In another embodiment, the condition is a dyskinesia associated with dopamine agonist therapy.

In a specific example, the psychiatric disorder is selected from the group consisting of schizophrenia, such as delusional, dissociative, nervous, undifferentiated or residual; schizophrenia-like disorder; schizophrenic a condition, such as delusional or depressive; paranoia; a substance-induced psychiatric disorder, such as a psychosis induced by alcohol, amphetamine, marijuana, cocaine, hallucinogens, inhalants, opioids or phencyclidine; Delusional personality disorder; and schizophrenia type personality disorder.

The invention further provides a method of treating a drug addiction (e.g., alcohol, amphetamine, cocaine or opiate addiction) in a human, the method comprising administering to the human a formula I effective to treat addiction (such as drug addiction) Compound.

As used herein, the term "drug addiction" means an abnormal need for a drug and is typically characterized by a disorder of motivation, such as the urge to acquire a desired drug and the onset of a violent drug craving.

Other conditions that may be treated in accordance with the present invention are obsessive-compulsive disorder, non-insulin-demanding diabetes mellitus (NIDDM) and Tourette's syndrome and other delirium disorders as well as attention deficit/high activity disorders (ADHD).

A compound of formula I or a pharmaceutically acceptable salt thereof, in combination with one or more other drugs, including typical and atypical antipsychotic agents, for the treatment of a disease or condition useful in the compounds of the invention, wherein the combination of drugs together Individual drugs are safer or more effective. Additionally, the compounds of the invention may be used in combination with one or more other drugs that treat, prevent, manage, ameliorate or reduce the side effects or toxicity of the compounds of the invention or reduce the risk thereof. The combinations, uses, and methods of treatment of the present invention may also provide advantages in treating patients who are not sufficiently responsive or resistant to other known therapies.

These other drugs can be administered simultaneously or sequentially with the compounds of the invention by conventional routes and thus in the usual amounts. Accordingly, the pharmaceutical compositions of the present invention comprise a pharmaceutical composition comprising one or more additional active ingredients in addition to a compound of the present invention. Such combinations may be administered as part of a unit dosage form combination, or in the form of a kit or treatment regimen, wherein one or more other drugs are administered in a separate dosage form as part of a therapeutic regimen.

As used herein, the term "neuroleptic agent" refers to a drug that has an effect on the perception and behavior of an antipsychotic drug that reduces confusion, delusions, hallucinations, and psychomotor agonism in a psychotic patient. Also known as strong tranquilizers and antipsychotics, psychotropic inhibitors include (but are not limited to): typical antipsychotic drugs, including thiophene Further divided into aliphatic compounds, piperidine and piperazine ;sulfur (thioxanthene) (eg, cisordinol); butyl benzene (eg, fluoropropanol); dibenzoxazepine (eg, loxapine); dihydroindolone (eg, molindone); diphenylbutylpiperidine (eg, pimozide); and atypical antipsychotic drugs, including benzene Azole (e.g., risperidone), sertindole, olanzapine, quetiapine, osanetant, and ziprasidone.

Particularly preferred psychoactive inhibitors for use in the present invention are sputum, olanzapine, risperidone, quetiapine, aripiprazole, flupirtine, clozapine, ilarasi. Ketones and oxatanide.

As used herein and unless otherwise indicated, a "neurodegenerative disorder or condition" refers to a condition or condition caused by dysfunction and/or death of a neuron in the central nervous system. Administration of an agent that is effective in the treatment of such conditions and conditions: prevention of dysfunction or death of a neuron at risk in such conditions or conditions and/or compensation by a neuron at risk The dysfunction or loss of function caused by death enhances the function of impaired or healthy neurons. As used herein, the term "neurotrophic" refers to a substance or agent that has some or all of these properties.

All references (including publications, patent applications, and patents) cited herein are hereby incorporated by reference in their entirety in their entirety in the the the the the The maximum extent permitted by law).

The headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

Any and all examples or illustrative words (including "for example/for example/eg" and "as such" are used in this specification unless otherwise indicated. The invention is intended to be only illustrative of the invention and not to limit the scope of the invention.

The patent documents cited and incorporated herein are for convenience only and do not reflect any point of view of the validity, patentability, and/or enforceability of such patent documents.

The invention includes all modifications and equivalents of the subject matter described in the appended claims.

The invention disclosed herein is further illustrated by the following non-limiting examples.

Experimental part Preparation of the compounds of the invention

The compounds of formula I of the present invention can be prepared as described in the following reaction schemes.

The compound of formula I wherein L is -CH=CH- or -CH ₂ -CH ₂ - can be prepared by the reaction sequence shown in Scheme 1.

Process 1

In particular, compounds of formula I wherein L is -CH ₂ -CH ₂ - can be prepared by hydrogenation using a transition metal catalyst such as palladium metal and a source of hydrogen such as hydrogen, ammonium hydrogencarbonate or cyclohexadiene. To reduce the olefin of formula I, wherein L is -CH=CH-. The olefin of the formula I wherein L is -CH=CH- may be in the presence of a suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a suitable solvent such as tetrahydrofuran. The Wittig reaction between the sulfonium salt of the formula IV and the aldehyde of the formula V is prepared. The salts of the formula IV are reacted with triphenylphosphine by a compound of the formula IV (see Scheme 1 above) by methods known to chemists skilled in the art and as described, for example, in WO-2011072696, WO-2011072694 and WO-2009152825. Easy to get. Aldehydes of formula V are commercially available or are available by methods described in the literature, see, for example, Organometallics (2011), 30(5), 1008-1012, Journal of Medicinal Chemistry (2010), 53(24), 8663- 8678; Chemical Communications (2010), 46 (35), 6554-6556, Journal of Medicinal Chemistry (2010), 53 (5), Science of Synthesis (2005), 15389-549. Journal of the Chemical Society (1932), Journal of the American Chemical Society (1941), 632654-5.

General method

Analytical LC-MS data was obtained using the following method:

Method 111:

The LC-MS is operated on a Sciex API 150EX equipped with an APPI source operating in positive ion mode. The HPLC consisted of a Shimadzu LC10-ADvp LC pump, an SPD-M20A PDA UV detector (operating at 254 nM) and a shimadzu CBM-20A system controller. The autosampler is Gilson 215. The Colomn oven was a Metalox model 200-C and the column temperature was 60 °C. Syringe: Gilson Model 841 (1 microliter ring).

The ELS detector is Sedere Sedex 85.

LC conditions: The column was Waters Symmetry C-18. 4.6 x 30 mm. 3.5 μm, operating at 60 ° C, a binary gradient consisting of 3.3 ml/min: solvent A: 100% H ₂ O, 0.05% TFA and solvent B: 95% ACN, 5% H ₂ O, 0.035% TFA

Injection volume: 10 μl (1 μl injected onto the column)

Gradient: 10% B to 100% B, within 2.4 minutes

10% B, within 0.4 minutes.

Total operating time: 2.8 minutes

Method 131:

The LC-MS is operated on a Sciex API 150EX equipped with an APPI source operating in positive ion mode. The HPLC consisted of a Shimadzu LC10-ADvp LC pump, an SPD-M20A PDA UV detector (operating at 254 nM) and a shimadzu CBM-20A system controller. Automatic take The sampler is Gilson 215. The Colomn oven was Jones Chromatography 7990R and the column temperature was 60 °C.

The ELS detector is Sedere Sedex 85.

LC conditions: The column was Waters Symmetry C-18. 4.6 x 30 mm. 3.5 μm, operating at 60 ° C, a binary gradient of 3.3 ml/min consisting of solvent A: H ₂ O and 0.05% v/v TFA and solvent B: methanol and 0.05% TFA

Injection volume: 10 μl (1 μl injected onto the column)

Gradient: 0.01 minutes 17% B (v/v)

0.27 minutes 28% B(v/v)

0.53 minutes 39% B(v/v)

0.80 minutes 50% B(v/v)

1.07 minutes 59% B(v/v)

1.34 minutes 68% B(v/v)

1.60 minutes 78% B(v/v)

1.87 minutes 86% B(v/v)

2.14 minutes 93% B(v/v)

2.38 minutes 100% B(v/v)

2.40 minutes 17% B(v/v)

2.80 minutes 17% B(v/v)

Total operating time: 2.8 minutes

Method 132

On the Sciex API150EX equipped with an APPI source operating in positive ion mode Operate LC-MS. The HPLC consisted of a Shimadzu LC10-ADvp LC pump, an SPD-M20A PDA UV detector (operating at 254 nM) and an SCL-10A system controller.

The autosampler is Gilson 215. The Colomn oven is Jones Chromatography 7990R and the ELS detector is Sedere Sedex 85.

LC conditions: The column was Waters Symmetry C-18. 4.6 x 30 mm. 3.5 μ, operating at 60 ° C, the binary gradient consisting of 2.5 ml/min: water + 0.05% TFA (A) and methanol + 0.05% TFA (B).

Gradient: 0.01 minutes 5% B

2.38 minutes 100% B

2740 minutes 5% B

2.80 minutes 5% B

Total operating time: 2.8 minutes

Method 350

The LC-MS is operated on a Sciex API 300 equipped with an APPI source operating in positive ion mode. The UPLC consists of a Waters Aquity consisting of a column manager, a binary solvent manager, a sample organizer, a PDA detector (operating at 254 nM), and an ELS detector.

LC conditions: The column was Waters Aquity UPLC BEHC-18. 2.1 x 50 mm. 1.7 μm, operating at 60 ° C, a binary gradient of 1.2 ml/min consisting of water + 0.05% TFA (A) and 95% acetonitrile (containing 5% water) + 0.03% TFA (B).

Total operating time 1.15 minutes

Preparative LC-MS purification was performed on a PE Sciex API 150EX instrument with atmospheric pressure chemical ionization. Column: 50 x 20 mm YMC ODS-A, particle size 5 microns; Method: Linear gradient elution with A:B = 80:20 to 0:100 in 7 minutes and at a flow rate of 22.7 ml/min. The fractionation of the eluted fraction was performed by shunt MS detection.

¹ H NMR spectra were recorded on a Bruker Avance AV500 instrument at 500.13 MHz or on a Bruker Avance Ultrashield plus instrument at 600.16 MHz. TMS was used as an internal reference standard. The chemical shift value is expressed in ppm. . The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintuple, h = sigmoid, dd = two sets of doublet, dt = two sets of triplet, dq = two sets of quadruple peaks, td = three sets of double peaks, tt = three sets of triplet, m = multiplet, br s = wide singlet and br = wide signal.

The abbreviations are based on the ACS Style Guide: "The ACS Styleguide-A manual for authors and editors" by Janet S. Dodd, 1997, ISBN:0841234620

Preparation of intermediates

The salts of the formula IV shown in Scheme 1 are by methods known to chemists skilled in the art and by the use of compounds of formula IV as described in, for example, WO-2011072696, WO-2011072694 and WO-2009152825 (see above 1) The reaction with triphenylphosphine is readily available. Aldehydes of formula V are commercially available or are available by methods described in the literature, see, for example, Organometallics (2011), 30(5), 1008-1012, Journal of Medicinal Chemistry (2010), 53(24), 8663- 8678. Chemical Communications (2010), 46 (35), 6554-6556, Journal of Medicinal Chemistry (2010), 53 (5), Science of Synthesis (2005), 15 389-549. Journal of the Chemical Society (1932), Journal of the American Chemical Society (1941), 63 2654-5.

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline-6-carbonitrile

To chlorinated (5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-ylmethyl)-triphenylhydrazine (0.222 g, 0.483 mmol) and 2-mercapto-quinoline-6-carbonitrile (80 mg, 0.4 mmol) in anhydrous tetrahydrofuran (6 mL, 80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (66 μL, 0.44 mmol) was added to the suspension (the reaction mixture temporarily became yellowish and the precipitate changed characteristics) and was at room temperature in an argon atmosphere. The mixture was stirred overnight. The mixture was rotary evaporated and the THF was evaporated. The solid was dissolved in DCM and chromatographed on EtOAc (EtOAc EtOAc) Pure product 2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-vinyl]-quinoline-6-carbonitrile is precipitated in one fraction (10): separated by filtration. Yield: 6 mg of a white solid.

The following intermediate was made in a similar manner: 2-[2-(5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-yl)-vinyl]-quinoline

2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-vinyl]-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline

2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-vinyl]-6-methoxy-quinoline

2-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline

2-[2-(8-ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-6-fluoro-quinoline

6-fluoro-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quin Porphyrin

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline

2-[2-(6-fluoro-quinolin-2-yl)-vinyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-ol

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-4-methyl-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-4-methoxy-quinoline

4-methoxy-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline

4-methoxy-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl] -quinoline

4-methyl-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline

2-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-4-methyl- quinoline

4-chloro-8-fluoro-2-[(E)-2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2- Base-vinyl]-quinoline

8-fluoro-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quin Porphyrin

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-7-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-4-fluoro-quinoline

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-7-fluoro-4-methoxy-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-7-fluoro-quinolin-4-ol

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-7-trifluoromethyl-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-4-methoxy-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-7-trifluoromethyl-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-quinolin-4-ol

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-5-fluoro-quinoline

7-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-vinyl]-6-isopropyl-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-5,7-difluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-5,6,8-trifluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6,8-difluoro-quinoline

6-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-[1,3] Oxazo[4,5-g]quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-8-methyl-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-fluoro-7-methyl-quinoline

6-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-2,2-difluoro-[1,3] Oxazo[4,5-g]quinoline

7-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline-6-carbonitrile

7-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-2,3-dihydro-[1,4] And [2,3-g]quinoline

6-chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline

6-chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-8-fluoro-quinoline

8-chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-methyl-quinoline

5,7-Dichloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-quinoline

Preparation of the compounds of the invention

Example 1: 2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-trifluoromethyl-quinoline

To chlorinated (5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-ylmethyl)-triphenylhydrazine (0.48 g, 1.0 mmol) and 6-trifluoromethyl-quinoline-2-carbaldehyde (0.24 g, 1.0 mmol) in anhydrous N,N-dimethylformamidine Add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL, 1.0 mmol) to a solution of the amine (25 mL, 320 mmol) (reaction mixture changed dark) and at room temperature in argon The mixture was stirred overnight under a gas atmosphere. The reaction mixture showed precipitation the next day.

The precipitate was filtered off. Wash with water and ether. It was dried by vacuum on a filter, followed by vacuum at 60 ° C for 2 hours. Filter cake: obtained the final product 2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl A white solid of 2-yl)-vinyl]-6-trifluoromethyl-quinoline. LC-MS: m/z = 369.7 (MH+). Rt = 1.96 min, method = 131.

The following compound was produced in a similar manner: 2-[(E)-2-(5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-yl)-vinyl]-quinoline LC-MS : m/z = 301.1 (MH+). Rt = 0.55 minutes, method = 1121.

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-trifluoromethoxy-quinoline LC-MS: m/z = 386.1, Rt = 1,97 min,

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-6-cyano-quinoline LC-MS: m/z = 327.3, Rt = 1,97 min,

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-7-methoxy-quinoline LC-MS: m/z = 332.1, Rt = 1, 22 min, method = 131

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-5-methoxy-quinoline LC-MS: m/z = 332.2, rt = 41, 41 min.

Example 2: 6-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-1,3-di Oxazo[4,5-g]quinoline

6-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-1,3-two Zyrazolo[4,5-g]quinoline (0.183 g, 0.530 mmol) was dissolved in EtOAc (1 mL, EtOAc). [B] p-Toluenesulfonate (0.296 g, 1.59 mmol; supplier = Avocado) was added and the reaction solution was stirred at 130 ° C under an argon atmosphere. Perform LCMS and show almost complete conversion. 0.100 g of [B] was added to the mixture and stirred at 130 ° C for 2 days.

Evaporate DMF. The solid was dissolved in 50 mL EtOAc and treated with 2 × 25 mL saturated NaHCO ₃ and extracted in 50 mL brine. The organic phase was rotary evaporated and EtOAc (EtOAc):EtOAc (EtOAc) Yield: 40 mg solids. LC-MS: m/z = 348.4 (MH+). Rt = 0.34 minutes, method = 350.

The following compound was prepared in a similar manner: 2-[2-(5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-yl)-ethyl]-quinoline LC-MS: m/z = 303, 4 (MH+). Rt = 0, 34 minutes, method = 11

2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-quinoline LC-MS: m/ z = 304.3 (MH+). Rt = 0, 46 minutes, method = 11

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-quinoline LC-MS: m/z = 304.3 (MH+). Rt = 0, 61 minutes, method = 131

2-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-6-methoxy-quinoline LC-MS: m/z = 334, 5 (MH+). Rt = 0, 62 minutes, method = 131

2-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS : m/z = 319, 1 (MH+). Rt = 0, 71 minutes, method = 131

2-[2-(8-ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-6-fluoro-quinoline LC-MS: m/z = 335, 2 (MH+). Rt=1, 12 minutes, method=131

6-fluoro-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quin Poleine LC-MS: m/z = 337, 5 (MH+). Rt = 0, 96 minutes, method = 131

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/ z = 303, 5 (MH +). Rt = 0, 76 minutes, method = 131

2-[2-(6-fluoro-quinolin-2-yl)-ethyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-ol LC - MS: m/z = 323, 1 (MH+). Rt = 0, 41 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-4-methyl-quinoline LC-MS: m/z = 318, 2 (MH+). Rt = 0, 83 minutes, method = 131

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-4-methoxy-quinoline LC-MS: m/z = 334, 5 (MH+). Rt = 0, 9 minutes, method = 131

4-methoxy-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS : m/z = 319, 2 (MH+). Rt = 0, 93 minutes, method = 131

4-methoxy-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl] - Quinoline LC-MS: m/z = 349, 1 (MH+). Rt = 1, 01 minutes, method = 131

4-methyl-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/z = 303, 4 (MH+). Rt = 0, 85 minutes, method = 131

2-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-methyl- Quinoline LC-MS: m/z = 333, 2 (MH+). Rt = 0, 95 minutes, method = 131

4-chloro-8-fluoro-2-[(E)-2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2- ))-vinyl]-quinoline LC-MS: m/z = 369, 2 (MH+). Rt = 1, 98 minutes, method = 131

8-fluoro-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quin Poleine LC-MS: m/z = 337, 5 (MH+). Rt = 1, 32 minutes, method = 131

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-7-fluoro-quinoline LC-MS: m/z = 321, 8 (MH+). Rt = 0, 43 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6-fluoro-quinoline LC-MS: m/z = 322, 1 (MH+). Rt = 0, 44 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-4-fluoro-quinoline LC-MS: m/z = 321, 9 (MH+). Rt = 0, 44 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-7-fluoro-4-methoxy-quinoline LC-MS: m/z = 352, 3 (MH+). Rt = 0, 87 minutes, method = 131

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-7-fluoro-quinolin-4-ol LC-MS: m/z = 338, 4 (MH+). Rt = 1, 08 minutes, method = 131

2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-vinyl]-7-trifluoromethyl-quinoline LC-MS: m/z = 370, 2 (MH+). Rt = 0, 79 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6-fluoro-4-methoxy-quinoline LC-MS: m/z = 352, 3 (MH+). Rt = 0, 9 minutes, method = 131

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-7-trifluoromethyl-quinoline LC-MS: m/z = 372, 3 (MH+). Rt = 0, 61 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6-fluoro-quinolin-4-ol LC-MS: m/z = 338, 1 (MH+). Rt=1,05 minutes, method=131

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-5-fluoro-quinoline LC-MS m/z = 322,1 (MH+). Rt=1, 25 minutes, method=131

7-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-quinoline LC-MS: m/z = 338, 3 (MH+). Rt = 1, 82 minutes, method = 132

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-ethyl]-6-isopropyl-quinoline LC-MS: m/z = 346, 2 (MH+). Rt = 0, 47 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-5,7-difluoro-quinoline LC-MS: m/z = 339, 8 (MH+). Rt = 0, 57 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-5,6,8-trifluoro-quinoline LC-MS: m/z = 358, 4 (MH+). Rt = 0, 67 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6,8-difluoro-quinoline LC-MS: m/z = 339, 7 (MH+). Rt = 0, 6 minutes, method = 350

6-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-[1,3] Zoxao[4,5-g]quinoline LC-MS: m/z = 348, 4 (MH+). Rt = 0.34 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6-fluoro-8-methyl-quinoline LC-MS: m/z = 336, 3 (MH+). Rt = 0, 57 minutes, method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6-fluoro-7-methyl-quinoline LC-MS: m/z = 336, 3 (MH+). Rt = 0, 41 minutes, method = 350

6-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-2,2-difluoro-[1,3] Zoxao[4,5-g]quinoline LC-MS: m/z = 384, 2 (MH+). Rt = 1, 6 minutes, method = 131

7-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-quinoline-6-carbonitrile LC-MS: m/z = 363, 2 (MH+). Rt = 1, 61 minutes, method = 131

7-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-2,3-dihydro-[1,4] And [2,3-g]quinoline LC-MS: m/z = 362, 3 (MH+). Rt = 0, 82 minutes, method = 131

6-chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-quinoline LC-MS: m/z = 338, 3 (MH+). Rt = 1, 31 minutes, method = 131

6-chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-8-fluoro-quinoline LC-MS: m/z = 356, 2 (MH+). Rt = 1, 72 minutes, method = 131

8-chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-6-methyl-quinoline LC-MS: m/z = 352, 4 (MH+). Rt = 1, 7 minutes, method = 131

5,7-Dichloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-ethyl]-quinoline LC-MS: m/z = 372, (MH+). Rt = 2, 01 minutes, method = 131

Pharmacological test

PDE10A Enzyme

Active PDE10A enzymes are prepared in a number of ways for PDE analysis (Loughney, K. et al, Gene 1999, 234 , 109-117; Fujishige, K. et al, Eur J Biochem. 1999, 266, 1118-1127 and Soderling, S. et al., Proc. Natl. Acad. Scl . 1999, 96 , 7071-7076). PDE10A can be expressed as a full-length protein or a truncated protein, provided that it exhibits a catalytic domain. PDE10A can be prepared in different cell types, such as insect cells or E. coli. An example of a method for obtaining catalytically active PDE10A is to amplify the catalytic domain of human PDE10A (registered amino acid 440-779 of the sequence numbered NP 006652) from total human brain total RNA by standard RT-PCR and will It was cloned at the BamH1 and Xho1 sites of the pET28a vector (Novagen). Performance in E. coli was performed according to standard protocols. Briefly, the expression plastids were transformed into BL21 (DE3) E. coli strains, and 50 mL cultures were inoculated with cells allowed to grow to OD600 0.4-0.6, followed by induction of protein expression with 0.5 mM IPTG. After the induction, the cells were incubated overnight at room temperature, after which the cells were collected by centrifugation. The cells expressing PDE10A were resuspended in 12 mL (50 mM TRIS-HCl-pH 8.0, 1 mM MgCl ₂ and protease inhibitor). The cells were lysed by sonication and after all cells were dissolved, Triton X100 was added according to the Novagen protocol. PDE10A was partially purified on Q Sepharose and the most active fractions were pooled.

PDE10A inhibition analysis

The PDE10A assay can be performed, for example, as follows: in a fixed amount of related PDE enzyme (sufficient to convert 20-25% cyclic nucleotide acceptor), buffer (50 mM HEPES 7.6; 10 mM MgCl ₂ ; 0.02% Tween 20), 0.1 mg/ Analysis was performed in ml BSA, 225 pCi ³ H labeled cyclic nucleotides, 60 μL samples of cAMP-labeled cAMP (to a final concentration of 5 nM) and varying amounts of inhibitor. The reaction was initiated by the addition of a cyclic nucleotide acceptor and the reaction was allowed to proceed for one hour at room temperature and then terminated by mixing with 15 μL of 8 mg/mL cesium citrate SPA beads (Amersham). The beads were allowed to settle in the dark for one hour and then the plates were counted in a Wallac 1450 Microbeta counter. The measurement signal may be converted without inhibition control (100%) of the active and may be used with respect to the Xlfit extension to EXCEL ₅₀ values _were calculated IC.

Phenylcyclohexylpiperidine (PCP) induced high activity

Male mice weighing 20-25 g (NMRI, Charles River) were used. Eight mice were used in each group receiving the test compound (5 mg/kg) + PCP (2.3 mg/kg), including a control group receiving the test compound + PCP or a vehicle-only injection. The injection volume is 10 ml/kg. Experiments were performed in undisturbed rooms under normal light conditions. The test substance was injected via oss 60 minutes before the injection of PCP (subcutaneous administration).

Immediately after the injection of PCP, the mice were individually placed in specially designed test cages (20 cm x 32 cm). The activity was measured by a 5 x 8 infrared source and a photocell spaced 4 cm apart. The beam passes through the cage 1.8 cm above the bottom of the cage. The recording of the kinetic count requires the interruption of adjacent beams, thus avoiding the counting induced by the resting activity of the mouse.

The phase of exercise lasting for 1 hour was recorded at 5 minute intervals. The drug effect was calculated in the following manner based on the total count during the 1-hour behavioral test phase: the mean motility induced by the vehicle treatment in the absence of PCP was used as the baseline. Therefore, the 100% effect of PCP minus the baseline is calculated as the total motility count. Therefore, the response of the group receiving the test compound was determined by subtracting the baseline from the total motility count to compare with the parallel PCP. The percentage of similar results recorded in the group. The percentage of reaction was converted to percent inhibition.

Claims (4)

A compound selected from the group consisting of 7-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin -2-yl)ethyl)-2,3-dihydro-[1,4] And [2,3-g]quinoline and 6-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)ethyl)-[1,3] Zoxao[4,5-g]quinoline, or a pharmaceutically acceptable salt thereof. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical product. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. A use according to the compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a neurodegenerative disorder or a psychiatric disorder.